US3346577A - Method for the preparation of 4-amino-3 (2h) pyridazinones - Google Patents
Method for the preparation of 4-amino-3 (2h) pyridazinones Download PDFInfo
- Publication number
- US3346577A US3346577A US493602A US49360265A US3346577A US 3346577 A US3346577 A US 3346577A US 493602 A US493602 A US 493602A US 49360265 A US49360265 A US 49360265A US 3346577 A US3346577 A US 3346577A
- Authority
- US
- United States
- Prior art keywords
- pyridazinone
- amino
- grams
- reaction
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 15
- VROMXVIODDASTK-UHFFFAOYSA-N 5-amino-1h-pyridazin-6-one Chemical class NC1=CC=NNC1=O VROMXVIODDASTK-UHFFFAOYSA-N 0.000 title description 10
- 238000002360 preparation method Methods 0.000 title description 2
- -1 4-AMINO-O(2H)PYRIDAZINONE DERIVATIVE Chemical class 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 3
- ZUUYZUYBEYIAAF-UHFFFAOYSA-N 4-amino-6-chloro-2-methylpyridazin-3-one Chemical compound CN1N=C(Cl)C=C(N)C1=O ZUUYZUYBEYIAAF-UHFFFAOYSA-N 0.000 description 3
- 241000194017 Streptococcus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 2
- YDSWOVPIKMUQTC-UHFFFAOYSA-N 4-amino-N-(6-oxopyridazin-1-yl)benzenesulfonamide Chemical class S(=O)(C1=CC=C(C=C1)N)(=O)NN1N=CC=CC1=O YDSWOVPIKMUQTC-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GTRCGBDJLMQGJR-UHFFFAOYSA-N 3-amino-4,5-dimethyl-n-(1,2-oxazol-3-yl)benzenesulfonamide Chemical compound NC1=C(C)C(C)=CC(S(=O)(=O)NC2=NOC=C2)=C1 GTRCGBDJLMQGJR-UHFFFAOYSA-N 0.000 description 1
- NKNXAPVAMHOXNP-UHFFFAOYSA-N 4-amino-2,6-dimethoxy-n-pyrimidin-2-ylbenzenesulfonamide Chemical compound COC1=CC(N)=CC(OC)=C1S(=O)(=O)NC1=NC=CC=N1 NKNXAPVAMHOXNP-UHFFFAOYSA-N 0.000 description 1
- HMLADOWYUKWPEO-UHFFFAOYSA-N 4-amino-N-(3-methoxy-6-oxopyridazin-1-yl)-2-methylbenzenesulfonamide Chemical compound CC1=C(S(=O)(=O)NN2N=C(C=CC2=O)OC)C=CC(=C1)N HMLADOWYUKWPEO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100243951 Caenorhabditis elegans pie-1 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001646716 Escherichia coli K-12 Species 0.000 description 1
- 102000010029 Homer Scaffolding Proteins Human genes 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960000973 sulfadimethoxine Drugs 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- VLYWMPOKSSWJAL-UHFFFAOYSA-N sulfamethoxypyridazine Chemical compound N1=NC(OC)=CC=C1NS(=O)(=O)C1=CC=C(N)C=C1 VLYWMPOKSSWJAL-UHFFFAOYSA-N 0.000 description 1
- 229960004936 sulfamethoxypyridazine Drugs 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
Definitions
- the present invention relates to novel sulfanilylaminopyridazinone derivatives, their intermediates and a process for producing the same. More particular-1y it relates to 4-sulfanilylamino-3 (2H) pyridazinone derivatives, their intermediates and a process for producing the same.
- Another object of the present invention is to provide a novel process for producing the sulfanilylaminopyridazinone derivatives and their intermediates.
- novel sulfanilylaminopyridazinone derivatives of the present invention are represented by the general Formula I.
- R represents a member selected from the group consisting of hydrogen atom and lower alkyl radicals and R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals.
- R2 RNEGsmNH ⁇ N I f o wherein R represents an acyl radical, R represents a member selected from the group consisting of hydrogen 3,346,577 l sten-red 0a. 10, 1967 atom and lower alkyl radicals and R represents a member selected from the group consisting of halogen atom and lower alkoxy radicals, followed by hydrolysis.
- H (IV) HrNU wherein R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals, in the presence of an alkali hydroxide or an alkoxide.
- R represents a member selected from the group consisting of halogen atoms and lower lalkoxy radicals and R represents a lower alkyl radical
- R represents a lower alkyl radical
- R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals and R represents a member selected from the group consisting of amino radical and radicals capable of being converted to amino radical, followed by conversion of 4-substituent in the resulting 2-lower alkyl-4-substituted-3 (2H) pyridazinone into 4-amino radical in the case when R is not amino radical in the above definition.
- R represents a lower alkyl radical
- the first step in producing the compounds of the present invention usually involves the reaction of a 4- amino-3(2 H)pyridazinone derivatives with a p-acylaminobenzenesulfonyl halide.
- Reaction conditions to be employed are substantially similar to those which are conventionally employed for the production known sulfanilylarnide compounds, e.g. sulfanilylaminodiazine, sulfanilylaminoisoxazole.
- both of the above indicated reactants in approximately equimolar ratio are reacted at a temperature of from room temperature, i.e. C. to 100 C., more preferably from C. to 60 C., in the presence or absence of a solvent.
- the reaction which takes lace herein is shown by the following equation.
- R represents a member selected from the group consisting of hydrogen atom and lower alkyl radicals
- R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals
- X represents a halogen atom
- R represents an acyl radical.
- hydrogen halide is byproduced during the reaction, and therefore, it is particularly recommended to carry out the reaction in the presence of a hydrogen halide-acceptor, such as pyridine, alkali carbonate, alkali bicarbonate, etc.
- Suitable solvents if used for the instant reaction, include water, methanol, ethanol, propanol, etc.
- Pyridine is particularly suitable because it takes a part as solvent and hydrogen halide-acceptor.
- aqueous or alcoholic solution of a dilute acid or a dilute alkali solu- 'tion e.g. 1% to 40% solution
- a short period of time e.g. from 10 minutes to 5 hours
- the hydrolysis reaction can be advantageously carried out at a temperature of from C. to C. for a period of from 0.5 to 1.5 hours.
- the acyl radical which is attached to protect the pamino portion of the said acylaminobenzenesulfonyl halide may be formyl, acetyl, propionyl, butyryl, ethoxycarbonyl, benzoyl, etc.
- the halogen atom which constitutes the sulfonyl halide portion may be chlorine or bromine.
- R in the general Formulae I, II and III include hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl (including isometric structures) radicals and those of R include chlorine and bromine atoms and methoxy, ethoxy, n-propoxy, isopropoxy, butoxy (including isomeric structures) radicals.
- 4-sulfanilylamino-3(2H)pyridazinone derivatives are novel compounds, and they are colorless crystalline substances, and soluble in dilute acid and alkali aqueous solutions, and difiicultly soluble in benzene, chloroform and ethyl ether. They are easily soluble in hot alcohol and recrystallizable from ethanol or methanol.
- R and R have the same meanings as identified above, from 4-substituted-3 (2H)pyridazinone derivative of the general Formula VII,
- the reaction may be proceeded at a temperature below 200 C. and it can be proceeded at such a low temperature as room temperature in the case when an aqueous alkali hydroxide solution is utilized.
- amination after alkylation is necessary, and the amination may be conducted without isolating the alkylated product.
- the amination reaction may be conducted according to the conventional method depending upon the kinds of the radical capable of being converted to amino radical in the 4-position. For example, hydrolysis may be conducted in the case when the radical is acylamino radical and treatment wtih ammonia may be conducted in the case when the radical is halogen atom.
- the compounds represented by the general Formula VI are novel compounds and they are colorless crystalline substance, and easily soluble in dilute acid soluble in Water and alcohol, and difficultly soluble in ether, and recrystallizable from ethyl acetate or acetone.
- R and X have the same meanings as identified above, by the reaction with an alcohol, the reaction is effected in the presence of an acid-acceptor.
- an acid-acceptor an inorganic or an organic basic substance such as alkali hydroxides, alkali carbonates, metal salts of an alcohol represented by the formula R OH wherein R is a lower alkyl and pyridine, may be utilized, in which sodium hydroxide and potassium hydroxide are most preferable.
- Reaction medium may be utilized in order to proceed the reaction more smoothly, and as the reaction medium, inert medium such as benzene, toluene, petroleum benzine, and nitrobenzene may be utilized.
- inert medium such as benzene, toluene, petroleum benzine, and nitrobenzene may be utilized.
- Alcohols which are the reactants, represented by the formula R OH wherein R is lower alkyl radical, may also be utilized. This reaction may be proceeded at a temperature below 300 C., and preferably at a temperature ranging from 100 C. to 200 C. in the case when an alkali hydroxide is utilized.
- the sulfanilylaminopyridazinone compounds of the present invention are valuable as chemotherapeutic agents, being effective against various kinds of pathogenic microorganisms in vitro.
- the present compounds show in vivo antibacterial activity stronger than the heretofore known long-acting sulfa drugs, and are less toxic.
- Table 1 shows the in vitro antimicrobial activity of the present compounds and the heretofore known sulfa drugs.
- Table 2 shows the comparative data of curvative effectiveness against Streptococcus group A type I infection in mice of the compounds of the present invention and the heretofore known sulfa drugs. The treatment is by days.
- Control Compound of the invention (Example 1) (Example 2) OH OIH 99. 9 9. 000 0C COO 0060 coo ooocn 0000! 0000! &
- SDM Sulfadimethoxine 2,6 dimethoxy-4-sulfanilylaminopyrimidine.
- SMP Sulfamethoxypyridazine 3 mebhoxy-6-srulfanilylaminopyridazine.
- Si Sulfisoxazole 3,4 dimethyl 5 sulfanilylaminoisoxazole.
- SP Sulfaphenazole 1 henyl-S-sulfanilytlaminopyrazole.
- Example I 2-methyl-4-sulfanilylamin0-6-methoxy-3 (2H) pyridazinone 2-methyl-4amino-6-methoxy 3(2H)pyridazinone (3.7 grams) is suspended in 40 ml. of dry pyridine and 6.2 grams of p-acetylaminobenzenesulfonyl chloride is added portionwise thereto below 10 C. with stirring. After completion of theaddition, the resulting solution is allowed to stand at room temperature overnight. The reaction mixture is poured into 2 times amount by volume of ice water, 12 ml.
- Example 2.-4-suZfanilylamin0-6-methoxy-3 (2H) pyridazinone 4-amino-6-methoxy-3(2H)pyridazinone (6 grams) is suspended in 60 ml. of dry pyridine and 20.8 grams of p-acetylaminobenzenesulfonyl chloride is added portionwise thereto and reacted as in the Example 1. The reaction mixture is poured into 2 times amount by volume of ice water, 47 ml. of 2 N sodium hydroxide solution is added thereto, and the pyridine is removed in vacuo. To the resulting residue, 100 ml.
- Example 5 -2-methyl-4-amin0 6-chloro-3 (2H) pyridazinone 4-acetamido-6-chloro-3 (2H)pyridazinone (1.5 grams) is dissolved in 12 ml. of 1 N sodium hydroxide solution and 1.2 grams of dimethyl sulfate is added dropwise thereto under cooling with stirring.
- Example 6 -2-methyl-4-amin.0-6-chZora-3(2H) pyridazinone 4-amino-6-chloro-3 (2H)pyridazinone (1.45 grams) is dissolved in 15 ml. of 1 N sodium hydroxide solution and 1.3 grams of dimethyl sulfate is added dropwise thereto under cooling with stirring. After stirring of 2 hours from completion of the dropping, precipitate formed is collected by filtration. Thus, 1.1 grams (yield 63%) of 2-methyl-4-amino-6-chloro-3(2H)pyridazinone, M.P. C., is obtained, which shows M.P. 146147 C. after recrystallization from ethyl acetate, and shows no depression of the melting point when mixed with the 2- methyl-4-amino 6 chloro-3(2H)pyridazinone specimen obtained in the Example 5.
- Example 7 -2-m ethyl-4-amino-6-methoxy-3 (2H) pyridazinone
- a mixture of 150 grams of 2-methyLl-4-amino-6-chloro- 3(2H)pyridazinone, 1300 ml. of methanol and 121.5 grams of potassium hydroxide (having 86% purity) is heated in an autoclave up to 130 C. for 10 hours. After cooling, the methanol is removed by distillation from the reaction mixture, the resulting residue is added with water, and the resulting water insoluble 2-methyl-4-amino-6- methoxy-3(2H)pyridazinone is collected by filtration and washed with water and dried.
- a process for producing a 4-amino-3 (2H)pyridazinone derivative of the formula wherein R is as precedingly defined and X represents a comprises the reaction of a 2-lower-alkyl-4-amino-6- hallogeno-3(2H)pyridazinone derivative of the formula wherein R is as precedingly defined and X represents a halogen atom, with an alcohol of the formula R OH wherein R is as precedingly defined, in an inert reaction medium containing a member selected from the group consisting of alkali metal hydroxide, alkali metal carbonate and pyridine, at a temperature from about to about 300 C.
- NICHOLAS S. RIZZO Primary Examiner.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
United States Patent O 3,346,577 METHOD FOR THE PREPARATION OF 4-AMINO-3(2H)PYRIDAZ1NONES Takenari Nakagome, Nishinomiya, and Toshiaki Komatsu, Toyonaka, Japan, assignors to Sumitomo Chemical Co., Ltd., Osaka, Japan N Drawing. Original application June 29, 1964, Ser. No. 379,014, now Patent No. 3,313,806, dated Apr. 11, 1967. Divided and this application Aug. 23, 1965, Ser. No. 493,602
2 Claims. (Cl. 260-250) This application is a division of application Ser. No. 379,014 which eventuated into Patent No. 3,313,806 on Apr. 11, 1967.
The present invention relates to novel sulfanilylaminopyridazinone derivatives, their intermediates and a process for producing the same. More particular-1y it relates to 4-sulfanilylamino-3 (2H) pyridazinone derivatives, their intermediates and a process for producing the same.
It is one object of the present invention to provide novel sulfanilylaminopyridazinone derivatives which are extremely valuable as chemotherapeutic agent due to their antibacterial activity.
It is also an object of this invention to provide intermediates for the above compounds.
Another object of the present invention is to provide a novel process for producing the sulfanilylaminopyridazinone derivatives and their intermediates.
The novel sulfanilylaminopyridazinone derivatives of the present invention are represented by the general Formula I.
HZN-GSWNH N N/ 0 where R represents a member selected from the group consisting of hydrogen atom and lower alkyl radicals and R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals.
These compounds can be obtained, according to the present invention, by the reaction of a 4-arnino-3 (2H) pyridazinone derivative of the general Formula II,
R2 RNEGsmNH \N I f o wherein R represents an acyl radical, R represents a member selected from the group consisting of hydrogen 3,346,577 l sten-red 0a. 10, 1967 atom and lower alkyl radicals and R represents a member selected from the group consisting of halogen atom and lower alkoxy radicals, followed by hydrolysis.
4-amino-3 (2H)pyridazinone derivatives of the above 5 indicated general Formula II, which are used for the production of the compounds of the present invention, can readily be produced by the followin processes.
The 4-amino-3 (2H) pyridazinone derivative of the general Formula 1V,
H (IV) HrNU wherein R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals, in the presence of an alkali hydroxide or an alkoxide. This is the novel process for producing the compounds of the general Formula IV, and the compounds having the lower alkoxy radicals as the R in the general Formula IV are novel compounds.
The novel 4-amino-3(2H)pyridazinone derivative of the general Formula VI,
wherein R represents a member selected from the group consisting of halogen atoms and lower lalkoxy radicals and R represents a lower alkyl radical, can readily be produced by the action of an alkylating agent, such as dialkyl sulfates and .alkyl halides, on a 4-substituted-3(2H) pyridazinone derivative of the general Formula VII,
(VII) wherein R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals and R represents a member selected from the group consisting of amino radical and radicals capable of being converted to amino radical, followed by conversion of 4-substituent in the resulting 2-lower alkyl-4-substituted-3 (2H) pyridazinone into 4-amino radical in the case when R is not amino radical in the above definition.
And the novel 4-amino-3 (2H)pyridazinone derivative of the general Formula VIII,
(VIII) wherein each of R and R represents a lower alkyl radical respectively, can readily be produced by the reaction of a novel 2-lower alkyl-4-amino-6-halogeno-3 (2H)pyridazinone derivative of the general Formula IX,
(I wherein R represents a lower alkyl radical and X represents a halogen atom, with an alcohol of the general Formula X,
R OH
wherein R represents a lower alkyl radical.
While these 4-amino-3 (2H)pyridazinone derivatives can be advantageously obtained by the above mentioned processes, they may be produced by any of other processes.
In accordance with the process of the present invention, the first step in producing the compounds of the present invention usually involves the reaction of a 4- amino-3(2 H)pyridazinone derivatives with a p-acylaminobenzenesulfonyl halide.
Reaction conditions to be employed are substantially similar to those which are conventionally employed for the production known sulfanilylarnide compounds, e.g. sulfanilylaminodiazine, sulfanilylaminoisoxazole. In the most preferred embodiment, both of the above indicated reactants in approximately equimolar ratio are reacted at a temperature of from room temperature, i.e. C. to 100 C., more preferably from C. to 60 C., in the presence or absence of a solvent. The reaction which takes lace herein is shown by the following equation.
wherein R represents a member selected from the group consisting of hydrogen atom and lower alkyl radicals, R represents a member selected from the group consisting of halogen atoms and lower alkoxy radicals, X represents a halogen atom and R represents an acyl radical. As apparent from the equation, hydrogen halide is byproduced during the reaction, and therefore, it is particularly recommended to carry out the reaction in the presence of a hydrogen halide-acceptor, such as pyridine, alkali carbonate, alkali bicarbonate, etc. Suitable solvents, if used for the instant reaction, include water, methanol, ethanol, propanol, etc. Pyridine is particularly suitable because it takes a part as solvent and hydrogen halide-acceptor. Thus formed 4(p-acylaminobenzenesulfonylamino)-3(2H)pyridazinone derivative of the general Formula III is then subjected to hydrolysis.
For example, it is heated together with an aqueous or alcoholic solution of a dilute acid or a dilute alkali solu- 'tion (erg. 1% to 40% solution) for a short period of time (e.g. from 10 minutes to 5 hours), thereby to give the corresponding 4-sulfanilylamino-3(2'H)pyridazinone derivatives of the general Formula I as the hydrolysis product. The hydrolysis reaction can be advantageously carried out at a temperature of from C. to C. for a period of from 0.5 to 1.5 hours.
The acyl radical which is attached to protect the pamino portion of the said acylaminobenzenesulfonyl halide may be formyl, acetyl, propionyl, butyryl, ethoxycarbonyl, benzoyl, etc. The halogen atom which constitutes the sulfonyl halide portion may be chlorine or bromine.
Typical examples of R in the general Formulae I, II and III, include hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl (including isometric structures) radicals and those of R include chlorine and bromine atoms and methoxy, ethoxy, n-propoxy, isopropoxy, butoxy (including isomeric structures) radicals.
Thus obtained 4-sulfanilylamino-3(2H)pyridazinone derivatives are novel compounds, and they are colorless crystalline substances, and soluble in dilute acid and alkali aqueous solutions, and difiicultly soluble in benzene, chloroform and ethyl ether. They are easily soluble in hot alcohol and recrystallizable from ethanol or methanol.
As to the process for producing 4-amino-3 (2H) pyridazinone derivatives of the general Formula II, which is the intermediate compounds of the present invention further mentioned as follows.
In the process for producing 4-amino-3(2H)pyridazinone derivative of the general Formula VI,
wherein R and R have the same meanings as identified above, from 4-substituted-3 (2H)pyridazinone derivative of the general Formula VII,
(VII) wherein R and R have the same meanings as identified above, by the action of an alkylating agent, as the alkylating agent, a conventional alkylating agent such as di-alkyl sulfates and alkyl halides can be utilized, and the reaction can be more accelerated in the presence of an acid-acceptor, such as alkali hydroxides and alkali carbonates. The reaction may be conducted in the presence or absence of a reaction medium, and as the reaction medium, inert medium such as Water, alcohol, acetone and benzene can be utilized.
The reaction may be proceeded at a temperature below 200 C. and it can be proceeded at such a low temperature as room temperature in the case when an aqueous alkali hydroxide solution is utilized.
In the case when a 3'(2H)pyridazinone derivative having a radical capable of being converted to amino radical in the 4-position is employed, amination after alkylation is necessary, and the amination may be conducted without isolating the alkylated product. The amination reaction may be conducted according to the conventional method depending upon the kinds of the radical capable of being converted to amino radical in the 4-position. For example, hydrolysis may be conducted in the case when the radical is acylamino radical and treatment wtih ammonia may be conducted in the case when the radical is halogen atom.
The compounds represented by the general Formula VI are novel compounds and they are colorless crystalline substance, and easily soluble in dilute acid soluble in Water and alcohol, and difficultly soluble in ether, and recrystallizable from ethyl acetate or acetone.
In the process for producing 4-amino-3'(2H)pyridazine derivative of the general Formula VIII,
(V III) wherein R and R have the same meanings as identified above, from 2,-lowera1kyl-4-amino-6-halogeno-3(2H) pyridazinone derivative of the general Formula 1X,
HzN
wherein R and X have the same meanings as identified above, by the reaction with an alcohol, the reaction is effected in the presence of an acid-acceptor. As the acid-acceptor, an inorganic or an organic basic substance such as alkali hydroxides, alkali carbonates, metal salts of an alcohol represented by the formula R OH wherein R is a lower alkyl and pyridine, may be utilized, in which sodium hydroxide and potassium hydroxide are most preferable.
' Reaction medium may be utilized in order to proceed the reaction more smoothly, and as the reaction medium, inert medium such as benzene, toluene, petroleum benzine, and nitrobenzene may be utilized. Alcohols, which are the reactants, represented by the formula R OH wherein R is lower alkyl radical, may also be utilized. This reaction may be proceeded at a temperature below 300 C., and preferably at a temperature ranging from 100 C. to 200 C. in the case when an alkali hydroxide is utilized.
The sulfanilylaminopyridazinone compounds of the present invention are valuable as chemotherapeutic agents, being effective against various kinds of pathogenic microorganisms in vitro. The present compounds show in vivo antibacterial activity stronger than the heretofore known long-acting sulfa drugs, and are less toxic. Table 1 shows the in vitro antimicrobial activity of the present compounds and the heretofore known sulfa drugs.
' TABLE 1 Minimum inhibitory concentration g.lcc.)Compounds of the invention Strain tested Exam- Exam- Exam- SDM SMP pie 1 ple 2 ple 3 Staphylococcus aureus 209p 6. 25 6. 25 6.25 6. 25 12.5 Streptococcus group A type I 12. 5 12. 5 12.5 25. 25.0 Diplococcus pneamoniae type I 12.5 12.5 6. 25 12.5 12.5 Escherichia coli 0-111 6.25 1. 56 25. 0 50.0 200 Escherichia coli K12. 1. 56 0.39 3.13 6. 25 1. 56 Salmonella typhi 58 50.0 25. 0 100 50. 0 25.0 Salmonella paratyphi 1015.--- 3. 13 3. 13 3. 13 1. 56 3. 13 Salmonella schottmuelleri 30 6. 25 3. 13 6. 25 6. 25 12. Shigella flezneri 2a 1. 56 0. 78 3.13 3.13 3.13 Proteus oalgaris K-S 0.20 0. 20 0.20 0.78 0. 39 Klebsiella pneumoniae 02 50. 0 12. 5 100 100 100 BC G 25. 0 6. 25 12. 5 100 200 Table 2 shows the comparative data of curvative effectiveness against Streptococcus group A type I infection in mice of the compounds of the present invention and the heretofore known sulfa drugs. The treatment is by days.
TABLE 2.STREPTOCOCCUS GROUP A TYPE I Survival, percent aiter 14 days Survivors] numbers of tested animals Mg./kg./day
Control Compound of the invention: (Example 1) (Example 2) OH OIH 99. 9 9. 000 0C COO 0060 coo ooocn 0000! 0000! &
(Example 3) SDM SMP
SIM
m the above-indicated tables, the abbreviation of the samples are as follows:
SDM: Sulfadimethoxine 2,6 dimethoxy-4-sulfanilylaminopyrimidine.
SMP: Sulfamethoxypyridazine 3 mebhoxy-6-srulfanilylaminopyridazine.
SIM. Sulfamethoxazole- 5 methyl-3-snlfanilylaminoisoxazole.
Si: Sulfisoxazole 3,4 dimethyl 5 sulfanilylaminoisoxazole.
SP: Sulfaphenazole 1 henyl-S-sulfanilytlaminopyrazole.
In order that those skilled in the art may better understand the invention, the following examples are given which are illustrative of the invention and are not intended for purposes of limitation.
Example I .2-methyl-4-sulfanilylamin0-6-methoxy-3 (2H) pyridazinone 2-methyl-4amino-6-methoxy 3(2H)pyridazinone (3.7 grams) is suspended in 40 ml. of dry pyridine and 6.2 grams of p-acetylaminobenzenesulfonyl chloride is added portionwise thereto below 10 C. with stirring. After completion of theaddition, the resulting solution is allowed to stand at room temperature overnight. The reaction mixture is poured into 2 times amount by volume of ice water, 12 ml. of 2 N sodium hydroxide solution is added thereto, and the solvent is removed in vacuo to form pale brown precipitate, which is collected by filtration and washed with water and dried. Thus, 7 .2 grams (yield 86%) of Z-methyl 4 (p-acetylaminobenzenesulfonylamino) 6-methoxy-3(2H)pyridazinone, M.P. 234-236 C. is obtained. Recrystallization from methanol affords colorless prisms, M.P. 242-243 C.
Elementary analysis for C I-I SO N is as follows- Calcd.: C, 47.73; H, 4.58; N, 15.90%. Found: C, 47.86; H, 4.67; N, 15.41%.
To 4.7 grams of the crude 2-methyl-4-(p-acetylaminobenzenesulfonylamino) 6 methoxy-3(2H)pyridazinone mentioned above, 30 m1. of 10% aqueous sodium hydroxide solution is added, and the resulting mixture is boiled under reflux for 45 minutes. After cooling, the mixture is acidified with acetic acid to form precipitate, which is collected by filtration and recrystallized from ethanol along with charcoal treatment to yield 3.2 grams (yield 75%) of 2-methyl 4 sulfanilylamino-6-methoxy3(2H) pyridazinone, colorless prisms, M.P. 215 C.
Elementary analysis for C H SO N is as follows- Calcd.: c, 46.45; H, 4.55; N, 18.06%. Found: c, 46.55; H, 4.55; N, 18.14%.
Example 2.-4-suZfanilylamin0-6-methoxy-3 (2H) pyridazinone 4-amino-6-methoxy-3(2H)pyridazinone (6 grams) is suspended in 60 ml. of dry pyridine and 20.8 grams of p-acetylaminobenzenesulfonyl chloride is added portionwise thereto and reacted as in the Example 1. The reaction mixture is poured into 2 times amount by volume of ice water, 47 ml. of 2 N sodium hydroxide solution is added thereto, and the pyridine is removed in vacuo. To the resulting residue, 100 ml. of 10% aqueous sodium hydroxide solution is added, and the resulting mixture is boiled under reflux for 1 hour, added with charcoal and filtered. The filtrate is acidified with acetic acid to. form precipitate, which is collected by filtration, and dried. Recrystallized from methanol, 5.7 grams (yield of 4-sulfanilylamino-6-methoxy 3(2H)pyridazinone, colorless needles, M.P. 249250 C. is obtained.
Elementary analysis for C H SO N is as follows- Called; C, 44.60; H, 4.08; N, 18.91%. Found: C, 44.83; H, 4.38; N, 18.88%.
Example 3.-2-methyl-4-sulfanilylamino-6-chlor0-3 (2H) pyridazinone 24methyl-4-amino 6 chloro-3 (2H)pyridazinone (10 grams) is suspended in 60 ml. of dry pyridine and 6.2 grams of p-acetylaminobenzenesulfonyl chloride is added portionwise thereto below 10 C. with stirring. After completion of the addition, the resulting solution is al lowed to stand at room temperature overnight. The reaction mixture is poured into 2 times amount by volume of ice water, 31 ml. of 2 N sodium hydroxide solution is added, and pyridine is removed in vacuo. To the resulting residue, 100 ml. of 10% aqueous sodium hydroxide solution is added and the resulting mixture is boiled under :reflux for 45 minutes, then acidified with acetic acid to form precipitate, which is collected by filtration to yield 11 grams of brown solid, M.P. 168-176 C. Recrystallization from methanol along with charcoal treatment affords 7 grams of 2-methyl-4-sulfanilylamino 6 chloro-3(2H) pyridazinone, colorless prisms, M.P. 185 186 C.
Elementary analysis for C H SO N Cl is as follows Calcd: C, 41.98; H, 3.52; N, 17.80%. Found: C, 42.20; H, 3.48; N, 17.62%.
Example 4.2-methyl-4-amino-6-methoxy-3 (2H) pyridazinone Calcd: C, 48.72; H, 5.62; N, 21.31%.
Found: C, 49.08; H, 5.75; N, 21.11%.
Then, 12 grams of thus obtained 2-methyl-4-acetamido- 6-rnethoxy-3(2H)pyridazinone is added with 100 ml. of 2 N hydrochloric acid and the resulting mixture is boiled under reflux for 1 hour. After cooling, the mixture is 8 made alkaline with sodium carbonate to form precipitate, which is collected by filtration, washed and dried. Thus, 7.7 grams (yield 82%) of 2-methyl-4-amino-6-methoxy- 3(2H)pyridazinone, M.P. 149'156 C. is obtained. Recrystallization from ethyl acetate affords colorless prisms, M.P. 157158 C.
Elementary analysis for C H O N is as follows- Calcd.: C, 46.44; H, 5.85; N, 27.08%. Found: C, 46.59; H, 6.08; N, 26.62%.
Example 5 .-2-methyl-4-amin0 6-chloro-3 (2H) pyridazinone 4-acetamido-6-chloro-3 (2H)pyridazinone (1.5 grams) is dissolved in 12 ml. of 1 N sodium hydroxide solution and 1.2 grams of dimethyl sulfate is added dropwise thereto under cooling with stirring.
Adding sodium hydroxide at intervals thereby keeping the pH value larger than 7, the reaction mixture is stirred for 2 hours to form precipitate, which is collected by filtration. Thus, 1.3 grams (yield 81%) of 2-methyl-4- acetamido 6 chloro-3(2H)pyrid-azinone, M.P. 208-209 C. is obtained.
Recrystallization from ethanol affords 1.1 grams of colorless leaflets.
Elementary analysis for CqHgOzNgCl is as follows Calcd.: C, 41.69; H, 4.00; N, 20.84%. Found: C, 41.87; H, 4.19; N, 20.55%.
Then, 6 grams of thus obtained 2-methyl-4-acetamido- 6-chloro-3 (2H)pyridazinone is added with 60 ml. of 2 N hydrochloric acid and the resulting mixture is boiled under reflux for 1 hour. After cooling, the mixture is made alkaline with sodium carbonate to form precipitate, which is collected by filtration, washed and dried. Thus, 4.3 grams (yield 91.5%) of 2-methyl-4-amino-6-chloro- 3(2H)pyridazinone, crystals, M.P. 146147.5 C. is obtained.
Recrystallization from ethyl acetate affords colorless needles, M.P. 148-148.5 C.
Elementary analysis for C H ON Cl is as follows Calcd.: C, 37.61; H, 3.79; N, 26.32%. Found: C, 38.17; H, 4.00; N, 26.12%.
Example 6.-2-methyl-4-amin.0-6-chZora-3(2H) pyridazinone 4-amino-6-chloro-3 (2H)pyridazinone (1.45 grams) is dissolved in 15 ml. of 1 N sodium hydroxide solution and 1.3 grams of dimethyl sulfate is added dropwise thereto under cooling with stirring. After stirring of 2 hours from completion of the dropping, precipitate formed is collected by filtration. Thus, 1.1 grams (yield 63%) of 2-methyl-4-amino-6-chloro-3(2H)pyridazinone, M.P. C., is obtained, which shows M.P. 146147 C. after recrystallization from ethyl acetate, and shows no depression of the melting point when mixed with the 2- methyl-4-amino 6 chloro-3(2H)pyridazinone specimen obtained in the Example 5.
Example 7.-2-m ethyl-4-amino-6-methoxy-3 (2H) pyridazinone A mixture of 150 grams of 2-methyLl-4-amino-6-chloro- 3(2H)pyridazinone, 1300 ml. of methanol and 121.5 grams of potassium hydroxide (having 86% purity) is heated in an autoclave up to 130 C. for 10 hours. After cooling, the methanol is removed by distillation from the reaction mixture, the resulting residue is added with water, and the resulting water insoluble 2-methyl-4-amino-6- methoxy-3(2H)pyridazinone is collected by filtration and washed with water and dried. Thus, 123.3 grams (yield 85%) of 2 methyll 4 amino 6 methoxy 3(2H)pyridazinone, M.P. C., is obtained. Recrystallization from methanol affords colorless prisms, M.P. 160 C.
Elementary analysis for C H O N is as follows- Calcd.: C, 46.44; H, 5.85; N, 27.08%. Found: C, 46.59; H, 6.08; N, 26.62%.
Example 8.2-methyl-4-amino-6-meth0xy-3 (2H) pyridazinone wherein R represents a member selected from the group consisting of halogen atoms and lower alkoxy and R represents lower alkyl, which comprises reacting a member selected from the group consisting of di-lower alkyl sulfate and lower alkyl halide with a 4-substituted-3(2H) pyridazinone derivative of the formula wherein R is as precedingly defined and R is a member selected from the group consisting of amino, halogen and acylamino, in the presence of a member selected from the group consisting of alkali metal hydroxide and alkali metal carbonate, at a temperature from ambient temperature up to 200 C. in an inert reaction medium to form the corresponding 2-lower alkyl-4-substi tuted-3(2H) pyridazinone, and treating the latter with ammonia when the 4-substituent is halogen and with aqueous alkali metal hydroxide when the 4-substituent is acylamino.
2. A process for producing a 4-amino-3 (2H)pyridazinone derivative of the formula wherein R is as precedingly defined and X represents a comprises the reaction of a 2-lower-alkyl-4-amino-6- hallogeno-3(2H)pyridazinone derivative of the formula wherein R is as precedingly defined and X represents a halogen atom, with an alcohol of the formula R OH wherein R is as precedingly defined, in an inert reaction medium containing a member selected from the group consisting of alkali metal hydroxide, alkali metal carbonate and pyridine, at a temperature from about to about 300 C.
References Cited FOREIGN PATENTS 4/ 1948 Great Britain.
OTHER REFERENCES Homer et al.: J. Chem. Soc., 1948, pages 2195 to 2201. Nakagome et al.: Jour. of Pharmaceutical Society (Japan), Vol.82, pages 1103 to 1109 (1962).
NICHOLAS S. RIZZO, Primary Examiner.
Claims (1)
1. A PROCESS FOR PRODUCING A 4-AMINO-O(2H)PYRIDAZINONE DERIVATIVE OF THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US493602A US3346577A (en) | 1963-07-01 | 1965-08-23 | Method for the preparation of 4-amino-3 (2h) pyridazinones |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3474663 | 1963-07-01 | ||
| JP3497563 | 1963-07-03 | ||
| US379014A US3313806A (en) | 1963-07-01 | 1964-06-29 | Sulfanilylaminopyridazinone derivatives and method for their production |
| US493602A US3346577A (en) | 1963-07-01 | 1965-08-23 | Method for the preparation of 4-amino-3 (2h) pyridazinones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3346577A true US3346577A (en) | 1967-10-10 |
Family
ID=33437151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US493602A Expired - Lifetime US3346577A (en) | 1963-07-01 | 1965-08-23 | Method for the preparation of 4-amino-3 (2h) pyridazinones |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3346577A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4837217A (en) * | 1985-04-19 | 1989-06-06 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, preparation thereof, and insecticidal, acaricidal, nematicidal, fungicidal compositions |
| US4874861A (en) * | 1984-11-29 | 1989-10-17 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, preparation thereof, and insecticidal, acaricidal, nematicidal, fungicidal compositions |
| US4877787A (en) * | 1983-06-23 | 1989-10-31 | Nissan Chemical Industries | Benzylthio pyridazinone derivatives, preparation thereof, and insecticidal acaricidal, fungicidal compositions |
| US4906627A (en) * | 1986-02-08 | 1990-03-06 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, and insecticidal, acaricidal and nematicidal compositions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB600532A (en) * | 1945-11-12 | 1948-04-12 | Walter Norman Haworth | Sulphanilamido pyridazones |
-
1965
- 1965-08-23 US US493602A patent/US3346577A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB600532A (en) * | 1945-11-12 | 1948-04-12 | Walter Norman Haworth | Sulphanilamido pyridazones |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4877787A (en) * | 1983-06-23 | 1989-10-31 | Nissan Chemical Industries | Benzylthio pyridazinone derivatives, preparation thereof, and insecticidal acaricidal, fungicidal compositions |
| US5026850A (en) * | 1983-06-23 | 1991-06-25 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, preparation thereof, and insecticidal, acaricidal, fungicidal compositions |
| US4874861A (en) * | 1984-11-29 | 1989-10-17 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, preparation thereof, and insecticidal, acaricidal, nematicidal, fungicidal compositions |
| US4837217A (en) * | 1985-04-19 | 1989-06-06 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, preparation thereof, and insecticidal, acaricidal, nematicidal, fungicidal compositions |
| US4906627A (en) * | 1986-02-08 | 1990-03-06 | Nissan Chemical Industries, Ltd. | Pyridazinone derivatives, and insecticidal, acaricidal and nematicidal compositions |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US2430439A (en) | Sulfonamido pyrimidines | |
| US2358031A (en) | Substituted thiadiazoles | |
| US3577441A (en) | Nitro substituted benzofurans | |
| US2435002A (en) | Process for the manufacture of para-aminobenzene-sulphonamidopyrimidines | |
| US3346577A (en) | Method for the preparation of 4-amino-3 (2h) pyridazinones | |
| US3862955A (en) | Process for the preparation of 1,2-benzisothiazolin 3-ones | |
| US3865825A (en) | Pyrimidinylphrazolone derivative and process of preparing the same | |
| US2767174A (en) | N-benzylidene and n-quinolylmethylene-substituted 2-aminobenzisothiazolones and processes for their preparation | |
| US4343942A (en) | Quinoxaline derivatives | |
| US3313806A (en) | Sulfanilylaminopyridazinone derivatives and method for their production | |
| US2350376A (en) | Process for the preparation of alloxazines and isoalloxazines | |
| US3084165A (en) | Quinone derivatives and processes for producing the same | |
| US4439436A (en) | 1,3-Dioxolo(4,5-G)quinoline compounds | |
| US2767192A (en) | Ketone hydrazones | |
| US4087528A (en) | 2,4-Diamino-5-benzylpyrimidines | |
| US3666754A (en) | 2-(5-nitrofuryl) nitrone derivatives | |
| US3420819A (en) | Novel sulfanilylaminopyridazinone derivatives and their production | |
| US3772294A (en) | Process for making pyrazolo-(3,4-d)-pyrimidines | |
| US3308118A (en) | Sulfanilamides | |
| US3180866A (en) | Substituted sulfapyrimidine derivatives | |
| US2980678A (en) | Pyrimidines | |
| US2882318A (en) | Hydroxy-methylindanone oximes and method | |
| US2845432A (en) | Benzamido and acetamido 4-amino-3-isoxazolidones and alkylated derivatives | |
| US3412093A (en) | New adenine derivatives and method for their preparation | |
| US3281412A (en) | Chemical compounds |